WO2012014011A1 - Compositions comprenant des polymères préparés à partir d'acides 2-hydroxyalkyliques - Google Patents

Compositions comprenant des polymères préparés à partir d'acides 2-hydroxyalkyliques Download PDF

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Publication number
WO2012014011A1
WO2012014011A1 PCT/IB2010/053383 IB2010053383W WO2012014011A1 WO 2012014011 A1 WO2012014011 A1 WO 2012014011A1 IB 2010053383 W IB2010053383 W IB 2010053383W WO 2012014011 A1 WO2012014011 A1 WO 2012014011A1
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composition
polymer
acid
catalyst
substituted
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PCT/IB2010/053383
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English (en)
Inventor
Michael Moeller
Lutz Asmus
Robert Gurny
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Universite De Geneve
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Priority to CA2806351A priority Critical patent/CA2806351C/fr
Priority to EP10752926.5A priority patent/EP2598553B1/fr
Priority to DK10752926.5T priority patent/DK2598553T3/da
Priority to PCT/IB2010/053383 priority patent/WO2012014011A1/fr
Priority to JP2013521232A priority patent/JP6147664B2/ja
Priority to ES10752926.5T priority patent/ES2581837T3/es
Priority to US13/811,986 priority patent/US9549985B2/en
Publication of WO2012014011A1 publication Critical patent/WO2012014011A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/66—Polyesters containing oxygen in the form of ether groups
    • C08G63/668—Polyesters containing oxygen in the form of ether groups derived from polycarboxylic acids and polyhydroxy compounds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/78—Preparation processes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
    • C08L67/04—Polyesters derived from hydroxycarboxylic acids, e.g. lactones

Definitions

  • polylactide such as the glass-transition temperature T g , crystallinity, lipophilicity, and degradation time can be changed by modifying the stereochemistry of the polymer, the molecular weight, or by copolymerization with a suitable copolymer.
  • T g glass-transition temperature
  • crystallinity crystallinity
  • lipophilicity and degradation time
  • polylactide can be modified for use in various applications, polylactide often forms solid aggregates that make it difficult to formulate bioactive agents with polylactide. Additionally, polylactide is not suitable for use as an injectable without formulating the polylactide as a nano- or microparticle, or without adding further excipients.
  • compositions comprising polymers prepared by melt polycondensation of 2-hydroxyalkyl acids, methods of making the compositions, and methods of using the compositions.
  • compositions comprising an admixture of a releasable agent and a polymer prepared by melt polycondensation of a substituted or unsubstituted C4-C32 2- hydroxyalkyl acid.
  • compositions comprising an admixture of a releasable agent and a copolymer prepared by melt co-polycondensation of a substituted or unsubstituted C4-C32 2-hydroxyalkyl acid and one or more of lactic acid or gly colic acid.
  • compositions comprising combining a polymer prepared by melt polycondensation of a substituted or unsubstituted C4-C32 2- hydroxyalkyl acid with a releasable agent.
  • Also disclosed is a method for the preparation of poly(hydroxyalkyl acid) polymers comprising a step of melt polycondensation of one or more substituted or unsubstituted C 4 - C32 2-hydroxyalkyl acid(s). Also disclosed are methods for delivering a bioactive agent to a subject, comprising administering to the subject an effective amount of a disclosed composition.
  • FIG. 1 is a plot of molecular weight versus reaction time for the polymerization of 2- hydroxyoctanoic acid using a tin catalyst.
  • FIG. 2 is a plot of molecular weight versus reaction time for the polymerization of 2- hydroxyoctanoic acid using sulfuric acid as a catalyst.
  • FIG. 3 is a plot of viscosity versus shear rate for polymers prepared by melt polycondensation of 2-hydroxyoctanoic acid of different molecular weight
  • FIG. 4 is a plot of viscosity versus shear rate for a neat polymer prepared by melt polycondensation of 2-hydroxyoctanoic acid, and the polymer blended with 1% and 5% NMP
  • FIG. 5 is a graph of the required injection force for native polymer, and for polymers blended with 1% and 5% NMP
  • FIG. 6 is a plot of in vitro haloperidol release from polymers prepared by melt polycondensation of 2-hydroxyoctanoic acid of different molecular weight
  • Ranges may be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
  • a weight percent of a component is based on the total weight of the formulation or composition in which the component is included.
  • a “releasable agent” refers to an agent that can be mixed together with a disclosed polymer and subsequently released therefrom, for example, as the polymer erodes.
  • a “bioactive agent” refers to an agent that has biological activity.
  • the biological agent can be used to treat, diagnose, cure, mitigate, prevent (i.e., prophylactically), ameliorate, modulate, or have an otherwise favorable effect on a disease, disorder, infection, and the like.
  • a “releasable bioactive agent” is one that can be released from a disclosed polymer.
  • Bioactive agents also include those substances which affect the structure or function of a subject, or a pro-drug, which becomes bioactive or more bioactive after it has been placed in a predetermined physiological environment.
  • a “polydispersity index” or “PDI” of a disclosed polymer refers to the weight averaged molecular weight (M w ) divided by the number averaged molecular weight (M n ). Both M w and M w can be readily determined by a variety of characterization techniques known in the art, including light scattering, size-exclusion chromatography (SEC), gel- permeation chromatography (GPC), viscosity measurements, among others.
  • These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a number of different polymers and agents are disclosed and discussed, each and every combination and permutation of the polymer and agent are specifically contemplated unless specifically indicated to the contrary.
  • the sub-group of A-E, B-F, and C-E are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D.
  • This concept applies to all aspects of this disclosure including, but not limited to, steps in methods of making and using the disclosed compositions.
  • steps in methods of making and using the disclosed compositions are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed.
  • the polymers of the invention are polymers prepared from alkyl-substituted lactic acid (or 2-hydroxyalkyl acids).
  • the polymers are prepared from linear monomers rather than ring-opening polymerization of cyclic di-lactone based monomers.
  • the resulting compositions can be substantially free from cyclic monomers, for example, substantially free from substituted or unsubstituted lactides, glycolides or caprolactones.
  • the C4-C32 2-hydroxyalkyl acid generally corresponds to the following structure:
  • R 1 is substituted or unsubstituted C2-C30 alkyl, and wherein R 5 is hydrogen or substituted or unsubstituted alkyl.
  • R 1 is preferably at least C 4 , so as to provide suitable hydrophobic character and reduce crystallinity of the polymer.
  • R 1 is C 4 -C 18 .
  • R 1 is C 4 to C 12 .
  • R 1 is C 6 (hexyl- substituted lactic acid), and R 5 is hydrogen.
  • the C 4 -C 32 2-hydroxyalkyl acid corresponds to the following structure:
  • each R 2 , R 3 , and R 4 is independently hydrogen, substituted or unsubstituted alkyl, alkoxy, halogen, cyano, alkyl ester, amide, or alkyl amide; and wherein R 5 is hydrogen or substituted or unsubstituted alkyl.
  • the C 4 -C 32 2-hydroxyalkyl acid can be 2-hydroxyethanoic acid, 2-hydroxypropanoic acid, 2-hydroxybutanoic acid, 2-hydroxypentanoic acid, 2- hydroxyhexanoic acid, 2-hydroxyheptanoic acid, 2-hydroxyoctanoic acid, 2- hydroxynonanoic acid, 2-hydroxydecanoic acid, 2-hydroxyundecanoic acid, 2- hydroxydodecanoic acid, 2-hydroxytridecanoic acid, 2-hydroxytetradecanoic acid, 2- hydroxypentadecanoic acid, 2-hydroxyhexadecanoic acid, 2-hydroxyheptadecanoic acid, 2- hydroxyoctadecanoic acid, 2-hydroxynonadecanoic acid, 2-hydroxyicosanoic acid, 2- hydroxyhenicosanoic acid, 2-hydroxydocosanoic acid, 2-hydroxytricosanoic acid, 2- hydroxytetracosanoic acid, 2-hydroxypentaco
  • the C 4 -C 32 2-hydroxyalkyl acid can be 2-hydroxy-2- methylpropanoic acid, 2-hydroxy-2-methylbutanoic acid, 2-hydroxy-2-ethylbutanoic acid, 2-hydroxy-2-methylpentanoic acid, 2-hydroxy-2-ethylpentanoic acid, 2-hydroxy-2- propylpentanoic acid, 2-hydroxy-2-butylpentanoic acid, 2-hydroxy-2-methylhexanoic acid, 2-hydroxy-2-ethylhexanoic acid, 2-hydroxy-2-propylhexanoic acid, 2-hydroxy-2- butylhexanoic acid, 2-hydroxy-2-pentylhexanoic acid, 2-hydroxy-2-methylheptanoic acid, 2-hydroxy-2-ethylheptanoic acid, 2-hydroxy-2-propylheptanoic acid, 2-hydroxy-2- butylheptanoic acid, 2-hydroxy-2-pentylheptanoic acid, 2-hydroxy-2-methylpropa
  • the C4-C32 2-hydroxyalkyl acid can be obtained from commercial sources or synthesized from commercially available starting materials.
  • the C4-C32 2- hydroxyalkyl acid can be prepared from a corresponding aldehyde according to Scheme 1.
  • the aldehyde can be added to NaHSC"3 in water, stirred for about 30 minutes, then a solution of NaCN (0.65 mol) in water can be added, followed by additional stirring for about 15 minutes.
  • the upper layer can be poured directly into sulfuric acid in water and heated at about 125 °C for about 3 hours, then can be poured into NaOH in water, and stirred for about 12 h.
  • the resultant alkaline solution can then be washed, and then acidified with HC1.
  • the polymer is prepared by a melt polycondensation reaction of the C4-C32 2- hydroxyalkyl acid and thus corresponds to the following general structure:
  • the polymer can be a polymer of any one or more of the C4-C32 2-hydroxyalkyl acids discussed above.
  • the C 4 - C32 2-hydroxyalkyl acid can have any suitable stereochemistry. All forms of the alkyl acid, including D-, L-, or D-,L- forms can be used, such as hexyl-substituted D-lactic acid, hexyl- substituted L-lactic acid, or hexyl substituted D,L-lactic acid, for example.
  • the polymer can be a homopolymer of the C4-C32 2-hydroxyalkyl acid, a copolymer of more than one C4-C32 2-hydroxyalkyl acids as discussed above, or a copolymer of the C 4 - C32 2-hydroxyalkyl acid and another hydroxy- carboxy lie acid.
  • Other acids that can be copolymerized with the C4-C32 2-hydroxyalkyl acid include one or more of lactic acid (D- or L-), glycolic acid, 3-hydroxybutyric acid, 4-hydroxybutyric acid, 4-hydroxyvaleric acid, 5-hydroxyvaleric acid, or 6-hydroxycapronic acid, or a combination thereof.
  • the copolymer comprises a mole ratio of about 50:50 (C 4 -C32 2- hydroxyalkyl acid: other acid), about 60:40 (C 4 -C32 2-hydroxyalkyl acid: other acid(s)), about 70:30 (C 4 -C32 2-hydroxyalkyl acid: other acid(s)), about 80:20 (C 4 -C32 2- hydroxyalkyl acid: other acid(s)), about 85 : 15 (C 4 -C32 2-hydroxyalkyl acid: other acid(s)), about 90: 10 (C 4 -C32 2-hydroxyalkyl acid: other acid(s)), or about 95:5 (C 4 -C32 2- hydroxyalkyl acid: other acid(s).
  • the copolymer can comprise a mole ratio of about 40:60 (C4-C32 2-hydroxyalkyl acid: other acid), about 30:70 (C4-C32 2- hydroxyalkyl acid: other acid(s)), about 20:80 (C 4 -C32 2-hydroxyalkyl acid: other acid(s)), about 15 :85 (C 4 -C 32 2-hydroxyalkyl acid: other acid(s)), about 10:90 (C 4 -C 32 2- hydroxyalkyl acid: other acid(s)), about 05 :95 (C 4 -C32 2-hydroxyalkyl acid: other acid(s)), Ratios in the region of about 10:90 (C 4 -C32 2-hydroxyalkyl acid: other acid) can be of interest, for example, in the formation of biodegradable films.
  • the polymer can also be a block copolymer comprising a block of the C 4 -C32 2- hydroxyalkyl acid, or even a C 4 -C32 2-hydroxyalkyl acid copolymerized with another acid as discussed above, together with another polymer block, such as a block of a hydrophilic polymer.
  • hydrophilic polymer are poly(ethylene glycol) (PEG) polymers, including alkoxypoly (ethylene glycol)s such as methoxypoly (ethylene glycol) (MPEG).
  • suitable PEG polymers include those with molecular weights of up to 5,000, such as PEG 200, PEG 400, PEG 500, PEG 1000, PEG 1500, PEG 2000, MPEG350, MPEG550, MPEG750, MPEG2000 and the like.
  • the block copolymers discussed above can in certain aspects exist as a micelle when dispersed in water, depending on the difference in hydrophilicity of the C 4 -C32 2- hydroxyalkyl acid block and the one or more other blocks.
  • a full micelle may not form, but at least partial phase separation of the blocks can exist.
  • the block copolymer is emulsified, and in further aspects there may even be complete phase segregation.
  • the releasable agent e.g., a releasable bioactive agent
  • the bioactive agent can also be adsorbed or conjugated to the micelle.
  • the polydispersity index (PDI) of the polymer will generally be higher than that expected for polymers prepared by ring-opening polymerization.
  • similar polymers prepared from ring-opening polymerization have a PDI of less than 1.35, generally less than 1.2.
  • the disclosed polymer has a polydispersity index (PDI) of greater than about 1.2.
  • the polymer has a polydispersity index (PDI) of at least 1.35.
  • the polymer has a polydispersity index (PDI) of at least 1.4.
  • the polymer has a polydispersity index (PDI) of at least 1.48. In a further aspect the polymer has a polydispersity index (PDI) of at least 1.6. In a further aspect the polymer has a polydispersity index (PDI) of at least 1.8, for example at least 2.0.
  • the polymers according to the present invention having relatively high polydispersity index (PDI), have improved viscosity and solvent properties.
  • the polymer has a polydispersity index (PDI) of from about 1.2 to about 2.5, for example a polydispersity index (PDI) of from about 1.4 to about 2.5.
  • the polymer has a polydispersity index (PDI) of from about 1.2 to about 2.0. In a further aspect, the polymer has a polydispersity index (PDI) of from about 1.35 to about 2.0. In a further aspect, the polymer has a polydispersity index (PDI) of from about 1.4 to about 2.0, for example of from about 1.48 to about 2.0.
  • PDI polydispersity index
  • the polydispersity index (PDI) of the polymer prepared according to the invention can be modified to a certain extent (e.g. within a range of from about 1.2, or about 1.35, to about 2.0, or even higher) by varying polycondensation conditions, in particular by varying polymerization time, temperature, catalyst or catalyst concentration, in order to optimize viscosity and solvent properties of the polymer for a desired pharmaceutical application, for instance in order to improve injectability.
  • the molecular weight ( w ) of the polymer can vary significantly and can be up to about 60,000 Daltons.
  • the polymer has an M w of at least the actual molecular weight of the C4-C32 2-hydroxyalkyl acid dimer and up to about 60,000 Daltons.
  • the polymer has a molecular weight ( w ) of from 500 to 60,000 Daltons.
  • the polymer has a molecular weight ( w ) of from 1,000 to 60,000 Daltons.
  • the polymer has a molecular weight ( w ) of from 3,000 to 60,000 Daltons.
  • the polymer has a molecular weight ( w ) of from 10,000 to 60,000 Daltons. In a further aspect, the polymer has a molecular weight ( w ) of from 28,000 to 60,000 Daltons. In other aspects, the polymer can have an M w of greater than 60,000 Daltons, particularly when the polymer is present as a copolymer of the C4-C32 2- hydroxy alky 1 acid and one or more other polymers, such as a hydrophilic polymer, as discussed above.
  • the polymer preferably has a lower M w , for example, less than about 15,000 Daltons. In one aspect, the polymer has an M w of less than about 10,000 Daltons. In a further aspect the polymer has an M w of less than about 8,000 Daltons, or even less than about 5,000 Daltons, for example from 500 to 5,000 Daltons. As discussed above, the polymer has a minimum molecular weight of at least the actual molecular weight of a dimer of the C4-C32 2-hydroxyalkyl acid.
  • the polymer may have a molecular weight ( w ) of from 500 to 15,000 Daltons, for example a molecular weight (M w ) of from 500 to 10,000 Daltons, for example from 1 ,000 to 10,000 Daltons, for example from 3,000 to 10,000 Daltons.
  • M w molecular weight
  • polymers can be modified or combined with a viscosity modifier to enable their use as a less viscous and even liquid composition. Polymers can also be heated up to lower their viscosity.
  • the polymer can have any desirable viscosity.
  • the viscosity of a neat polymer sample can be less than about 1000 Pa-s.
  • the viscosity of a neat polymer sample can be less than about 500 Pa-s.
  • the viscosity of a neat polymer sample can be less than about 100 Pa-s.
  • the viscosity of a neat polymer sample can be from about 0.001 to about 600 Pa-s (1 cp to 60,000 cp), and preferably from about 0.1 poise to about 20 Pa-s. Viscosities can be determined using methods known in the art, such as rheometry.
  • the polymer has alkyl-based side chains that reduce the crystallinity of the polymer.
  • the polymer will generally have a lower glass-transition temperature (T g ) than polymers prepared from lactic acid, for example.
  • T g glass-transition temperature
  • the alkyl-based side chains of the polymer essentially act as internal plasticizers, thereby reducing the crystallinity of the polymer. This property of the polymer also contributes to its ability to exist as a less viscous, or even liquid polymer.
  • the T g of the polymer depends on a number of factors, including the exact nature of the alkyl-based side chain, the nature of any co-monomers, if present, and molecular weight, among others.
  • the polymer exhibits a glass-transition temperature (T g ) of less than about 45 °C. In a further aspect, the polymer exhibits a glass- transition temperature (T g ) of less than about 20 °C.
  • the polymer can also have a T g of well below 0 °C. Glass transition temperatures (Tg) can be measured with a differential scanning calorimeter (DSC).
  • DSC differential scanning calorimeter
  • the polymer is prepared by melt poly condensation which can be carried out with or without catalyst.
  • the procedure involves adding an effective amount of a catalyst to the C4-C32 2-hydroxyalkyl acid (and any comonomers), and heating the mixture up to at least a temperature effective to melt the mixture, and maintaining this temperature for an effective amount of time to achieve polymerization (e.g., to achieve a desired degree of polymerization).
  • An inert atmosphere and/or vacuum can be used during the polymerization.
  • polymerization temperatures can range from above 100 °C to well over 200 °C, depending on the monomer, catalyst, and other conditions. In one aspect a temperature in the range of from about 100 °C to about 250 °C may be used, for example a temperature in the range of from about 120 °C to about 200 °C.
  • polymerization times can vary greatly from a few hours or less to over 12 hours, again depending on the desired degree of polymerization, catalyst, temperature, etc.
  • it can be desirable to perform the polymerization under vacuum to support removal of water from the reaction mixture or to avoid altering the molecular weight of the polymer (and therefore viscosity) at later stages of the polymerization.
  • Polymerization conversions and degrees of polymerizations (DP) can be determined by 1H NMR analysis.
  • Molecular weights and polydispersities can be determined by gel permeation chromatography (GPC), among other methods.
  • the polymerization is carried out with an effective amount of a catalyst.
  • An effective amount of the catalyst will generally be at least 0.1 mol%, relative to the monomer(s).
  • the amount of catalyst can be any amount that results in a desired polymer, for example, up to 10 mol% or more.
  • a lower mol% catalyst can be desired, for example if the composition is desired for use as a pharmaceutical composition and the catalyst is a metallic catalyst that might be harmful in a subject or biological application above certain levels.
  • an amount of catalyst of from about 0.1mol% to about 2.0mol%, for example from 0.1mol% to 1.0mol%, for example from 0.1mol% to 0.5mol%, may be preferred.
  • the catalyst can be metallic, non-metallic, or enzymatic, including a variety of non-metallic organic catalysts.
  • Suitable metal catalysts include zinc powder, tin powder, aluminum, magnesium and germanium, metal oxides such as tin oxide (II), antimony oxide (III), zinc oxide, aluminum oxide, magnesium oxide, titanium oxide (IV) and germanium oxide (IV), metal halides such as tin chloride (II), tin chloride (IV), tin bromide (II), tin bromide (IV), antimony fluoride (III), antimony fluoride (V), zinc oxide, magnesium chloride and aluminum chloride, sulfates such as tin sulfate (II), zinc sulfate and aluminum sulfate, carbonates such as magnesium carbonate and zinc carbonate, borates such as zinc borates, organic carboxylates such as tin acetate (II),
  • Dibutyltin dilaurate DBTL
  • Sb 2 C Sb 2 C
  • Ti(IV)bu Ti(IV)iso
  • Tin catalysts, and other metallic catalysts have been widely used in ring-opening polymerisation techniques, and the use of tin, or other metallic, catalysts is known to leave residual amounts of tin, or other metal, in the polymer product (see for example, G. Schwach et al, Influence of polymerization conditions on the hydrolytic degredation of poly(DL-lactide) polymerized in the presence of stannous octoate or zinc-metal, Biomaterials, 23 (2002) 993-1002).
  • tin catalysts or other metallic catalysts For some applications, a potential drawback in the use of tin catalysts or other metallic catalysts is the risk of presence of residual amounts of metal catalyst or deriving metal salts, where the presence of even trace amounts of such metals or deriving metal salts may potentially have deleterious effects in pharmaceutical application.
  • Another potential drawback of the use of tin catalysts, or other metallic catalysts is the necessity for the use of organic solvents for the removal of the catalyst.
  • the catalyst is non-metallic, and thus the composition is substantially free from metal.
  • the catalyst is a non-tin catalyst, and thus the composition is substantially free from tin.
  • Non-metallic acids include a variety of inorganic and organic acids. The acid can be a weak acid or a strong acid. In some instances, the organic acid need not be removed from the composition prior to use. Weak acids can be preferred when the acid catalyst will not be removed from the composition.
  • organic acids examples include acetic acid, glacial acetic acid, methane sulfonic acid, ethane sulfonic acid, 1 -propane sulfonic acid, 1 -butane sulfonic acid, trifluoromethane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, p-xylene-2- sulfonic acid, naphthalene- 1 -sulfonic acid and naphthalene 2-sulfonic acid, and others.
  • Acetic acid and glacial acetic acid amongst others, which have FDA GRAS (Generally Recognized As Safe) designation, may be of particular interest when the catalyst will not be removed from the composition.
  • Suitable inorganic acids include acids such as, sulfuric acid, sulfurous acid, phosphoric acid, phosphonic acid and others.
  • the catalyst is an inorganic acid.
  • the catalyst is sulfuric acid.
  • the polymerization is effected without a catalyst.
  • use of a catalyst-free process avoids the need for any step of purification for removal of the catalyst, thereby further simplifying the process, and the resulting polymers are free of any residual catalyst. Accordingly, polymers prepared by the polycondensation process of the invention in the absence of a catalyst can be of particular interest for pharmaceutical applications.
  • the composition comprising the polymer and the releasable agent can be a liquid, solid, semi-solid, or gel. In some aspects, the composition is a liquid. Such compositions are useful as injectable compositions, or flowable compositions. In other aspects, viscosity modifiers, plasticizers, or other additives or excipients can be added to the composition to change the viscosity of the composition, or even make the composition liquid when it would otherwise be solid, as discussed below.
  • the releasable agent can be dissolved, dispersed, or otherwise mixed with the polymer and/or other additives and excipients, if present. In other aspects, the releasable agent can be contained within the polymer, for example, when the polymer is a micelle or has phase segregated morphology.
  • the composition can be applied to a number of subjects, plants, or articles and thereafter release the releasable agent onto or into the desired location.
  • the composition can be injected, for example, injected into a subject, sprayed, for example, sprayed onto a plant, rubbed, painted, spin-cast, or otherwise applied.
  • the composition comprising the polymer and the releasable agent can in various aspects comprise other components, such as viscosity modifiers.
  • viscosity modifiers include plasticizers, additives, and solvents. Solvents can be used to formulate the releaseable agent with the polymer if desired. These solvents can remain in the composition if desired.
  • the amount of other components, such as viscosity modifiers, that can be present in the composition can vary and will generally be less than about 50% by weight of the composition. In one aspect the viscosity modifier is present in an amount of from a trace amount up to 50% by weight of the composition. In a further aspect the viscosity modifier is present in an amount of from a trace amount up to 25% by weight of the composition.
  • the viscosity modifier is present in an amount of from a trace amount up to 20% by weight of the composition. In a further aspect the viscosity modifier is present in an amount of from a trace amount up to 15% by weight of the composition. In a further aspect the viscosity modifier is present in an amount of from a trace amount up to 10% by weight of the composition. In a further aspect the viscosity modifier is present in an amount of from a trace amount up to 5% by weight of the composition. In a further aspect the viscosity modifier is present in an amount of from a trace amount up to 1% by weight of the composition. A trace amount refers to about 1% or less, for example, 0.1 %, 0.2%>, or 0.5%>.
  • a variety of additives can be used in combination with the compositions, such as a water-soluble polymer such as polyethylene glycol, a protein, polysacharride, or carboxmethyl cellulose, a surfactant, a plasticizer, a high- or low-molecular- weight porosigen such as polymer or a salt or sugar, or a hydrophobic low-molecular- weight compound such as cholesterol or a wax.
  • a water-soluble polymer such as polyethylene glycol, a protein, polysacharride, or carboxmethyl cellulose
  • a surfactant such as polyethylene glycol, a protein, polysacharride, or carboxmethyl cellulose
  • a surfactant such as polyethylene glycol, a protein, polysacharride, or carboxmethyl cellulose
  • a surfactant such as polyethylene glycol, a protein, polysacharride, or carboxmethyl cellulose
  • a surfactant such as polyethylene glycol, a protein, polysacharride, or
  • another polymer prepared by melt polycondensation or melt co- poly condensation of a substituted or unsubstituted C4-C32 2-hydroxyalkyl acid, having a lower molecular weight, and a lower viscosity can be added to the composition to modify the viscosity of the polymer of the composition.
  • polymers of the invention can be used in combination with the polymers of the invention and can be present in the compositions.
  • examples include polyglycolide (PG), polylactide (PL), polycapro lactone (PCL), polyethylene glycol (PEG), polydioxanone (PDO), poly(D,L-lactide-co-glycolide) (D,L-PLG) and poly(L-lactide-co-glycolide) (L- PLG), poly(hydroxyl alkanoate) (PHA), and other biodegradable and biocompatible polymers.
  • PG polyglycolide
  • PLA polylactide
  • PCL polycapro lactone
  • PEG polyethylene glycol
  • PDO polydioxanone
  • PDO poly(D,L-lactide-co-glycolide)
  • L- PLG poly(L-lactide-co-glycolide)
  • PHA poly(hydroxyl alkanoate)
  • Biocompatible polymers that can be used include polyesters, poly ethers, polyanhydrides, polyamines, poly(ethylene imines) polyamides, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polybutylene, polyterephthalate, polyorthocarbonates, polyphosphazenes, polyurethanes, polytetrafluorethylenes (PTFE), polysuccinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyhydroxycellulose, polysaccharides, chitin, chitosan, hyaluronic acid, and copolymers, terpolymers and mixtures thereof. Synthetic polymers and/or natural polymers can be used as the second polymer in combination with the polymers of the invention. The polymers can be admixed together, or otherwise used in combination.
  • the lactide-based polymers can comprise any lactide residue, including all racemic and stereospecific forms of lactide, including, but not limited to, L-lactide, D-lactide, and D,L- lactide, or a mixture thereof.
  • Useful polymers comprising lactide include, but are not limited to poly(L-lactide), poly(D-lactide), and poly(DL-lactide); and poly(lactide-co-glycolide), including poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), and poly(DL-lactide- co-glycolide); or copolymers, terpolymers, combinations, or blends thereof.
  • Lactide/glycolide polymers can be made by ring opening of lactide and glycolide monomers. Additionally, racemic DL-lactide, L-lactide, and D-lactide polymers are commercially available.
  • the L-polymers are more crystalline and resorb slower than DL- polymers.
  • copolymers comprising glycolide and DL-lactide or L-lactide
  • copolymers of L-lactide and DL-lactide are commercially available.
  • homopolymers of lactide or glycolide are also commercially available.
  • plasticizers that can be used include all FDA approved, or GRAS designated, plasticizers, such as benzyl benzoates, cellulose acetates, cellulose acetate phthalates, chlorobutanol, dextrines, dibutyl sebacate, dimethyl sebacate, acetyl phthalates, diethyl phthalate, dibutyl phthalate, dipropyl phthalate, dimethyl phthalate, dioctyl phthalate, methyl cellulose, ethyl cellulose, hydroxylethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl celluloses, gelatine, glycerines, glyceryl monostearate, monoglycerides, mono- and di
  • a composition comprising the polymer and one or more viscosity modifiers can have any desirable viscosity.
  • such a composition can have a viscosity of from about 0.001 to about 200 Pa-s, preferably from about 0.001 to about 50 Pa-s, more preferably from about 0.001 to about 20 Pa-s (1 cP to 20,000 cP), and more preferably from about 0.1 Pa-s to about 20 Pa-s.
  • the polymer in neat form can have any suitable viscosity, and such a polymer can be combined with a viscosity modifier to provide a composition having a desired viscosity, such as a viscosity suitable for an injectable composition.
  • the polymer can erode and allows the agent in the composition to be released.
  • the polymer can also be biocompatible or biodegradable, and thus the polymer can erode in a biological fluid or tissue.
  • a variety of releasable agents can be used in the compositions. Generally, any agent for which release over time is desired can be used.
  • the releasable agent can be a bioactive agent, cosmetic substance, such as a lotion, or other substance, such as an agricultural product.
  • the releasable agent can be dissolved or dispersed in the polymer and can be present in any suitable amount, which will generally depend on the intended use of the composition. In a particular aspect the releasable agent is dissolved in the polymer.
  • the releasable agent is a bioactive agent.
  • a large variety of bioactive agents can be used with the compositions.
  • the bioactive agent can be blended, admixed, or otherwise combined with the polymer.
  • the bioactive agent can be preformulated, e.g., spray-dried with sugar, into a defined particle.
  • the bioactive compound can be fully dissolved in the polymer.
  • at least a portion of the bioactive agent can be dissolved in the polymer.
  • at least a portion of the bioactive agent can be dispersed in the polymer.
  • the admixing of the bioactive agent and the polymer can be carried out with or without an additional solvent (other than the polymer).
  • the admixing can be accomplished without the use of an additional solvent (other than the polymer).
  • a solvent removal step is not required after the admixing step.
  • the amount of bioactive agent incorporated into the composition varies depending upon a particular drug, the desired therapeutic effect and the desired time span. Because a variety of compositions are intended to provide dosage regimens for therapy for a variety of purposes, there is no critical lower or upper limit in the amount of drug incorporated into the composition. The lower limit will generally depend upon the activity of the drug and the time span of its release from the device. Those skilled in the pharmaceutical arts can determine toxic levels of a given drug as well as the minimum effective dose.
  • bioactive agent can be used, which are capable of being released from polymer into a subject.
  • a liquid or solid bioactive agent can be incorporated into the compositions described herein.
  • the bioactive agents can be water soluble or water- insoluble. In some aspects the bioactive agent may be moderately water soluble, and is preferably only slightly or very slightly water soluble.
  • the bioactive agents can include salts of the active ingredient. As such, the bioactive agents can be acidic, basic, or amphoteric salts. They can be nonionic molecules, polar molecules, or molecular complexes capable of hydrogen bonding.
  • the bioactive agent can be included in the compositions in the form of, for example, an uncharged molecule, a molecular complex, a salt, an ether, an ester, an amide, polymer drug conjugate, prodrug, or other form to provide the effective biological or physiological activity.
  • bioactive agents examples include, but are not limited to, small molecules, peptides, proteins such as hormones, enzymes, antibodies, antibody fragments, antibody conjugates, nucleic acids such as aptamers, iR A, siR A, DNA, R A, antisense nucleic acid or the like, antisense nucleic acid analogs or the like, VEGF inhibitors, macrocyclic lactones, dopamine agonists, dopamine antagonists, low-molecular weight compounds, high-molecular- weight compounds, or conjugated bioactive agents.
  • nucleic acids such as aptamers, iR A, siR A, DNA, R A, antisense nucleic acid or the like, antisense nucleic acid analogs or the like, VEGF inhibitors, macrocyclic lactones, dopamine agonists, dopamine antagonists, low-molecular weight compounds, high-molecular- weight compounds, or conjugated bioactive agents.
  • Bioactive agents contemplated for use in the disclosed compositions include anabolic agents, antacids, anti-asthmatic agents, anti- cholesterolemic and anti-lipid agents, anti-coagulants, anti-convulsants, anti-diarrheals, antiemetics, anti-infective agents including antibacterial, anitviral and antimicrobial agents, anti-inflammatory agents, anti-manic agents, antimetabolite agents, anti-nauseants, antineoplastic agents, anti-obesity agents, anti-pyretic and analgesic agents, anti-spasmodic agents, anti-thrombotic agents, anti-tussive agents, anti-uricemic agents, anti-anginal agents, antihistamines, appetite suppressants, biologicals, cerebral dilators, coronary dilators, bronchiodilators, cytotoxic agents, decongestants, diuretics, diagnostic agents, erythropoietic agents, expectorants, gastrointestinal sedatives, hyperglycemic agents,
  • bioactive agents include androgen inhibitors, polysaccharides, growth factors, hormones, anti-angiogenesis factors, dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, chlophedianol hydrochloride, chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine, codeine phosphate, codeine sulfate, morphine, mineral supplements, cholestyramine, N-acetylprocainamide, acetaminophen, acetylsalicylic acid, ibuprofen, phenyl propanolamine hydrochloride, caffeine, guaifenesin, aluminum hydroxide,
  • compositions include, but are not limited to, peptide drugs, protein drugs, therapeutic antibodies, desensitizing materials, antigens, anti-infective agents such as antibiotics, antimicrobial agents, antiviral, antibacterial, antiparasitic, antifungal substances and combinations thereof, antiallergenics, androgenic steroids, decongestants, hypnotics, steroidal anti-inflammatory agents, anti-cholinergics, sympathomimetics, sedatives, miotics, psychic energizers, tranquilizers, vaccines, estrogens, progestational agents, humoral agents, prostaglandins, analgesics, antispasmodics, antimalarials, antihistamines, cardioactive agents, nonsteroidal anti-inflammatory agents, antiparkinsonian agents, antihypertensive agents, ⁇ -adrenergic blocking agents, nutritional agents, and the benzophenanthridine alkaloids.
  • the agent can further be a substance capable of acting
  • bioactive agents include but are not limited to analgesics such as acetaminophen, acetylsalicylic acid, and the like; anesthetics such as lidocaine, xylocaine, and the like; anorexics such as dexadrine, phendimetrazine tartrate, and the like; antiarthritics such as methylprednisolone, ibuprofen, and the like; antiasthmatics such as terbutaline sulfate, theophylline, ephedrine, and the like; antibiotics such as sulfisoxazole, penicillin G, ampicillin, cephalosporins, amikacin, gentamicin, tetracyclines, chloramphenicol, erythromycin, clindamycin, isoniazid, rifampicin, and the like; antifungals such as amphotericin B, nystatin, ketoconazole, and
  • the bioactive agent can also be an immunomodulator, including, for example, cytokines, interleukins, interferon, colony stimulating factor, tumor necrosis factor, and the like; allergens such as cat dander, birch pollen, house dust mite, grass pollen, and the like; antigens of bacterial organisms such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyrogenes, Cory neb acterium diphteriae, Listeria monocytogenes, Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Neisseria meningitides, Neisseria gonorrhoeae, Streptococcus mutans, Pseudomonas aeruginosa, Salmonella typhi, Haemophilus parainfluenzae, Bordetell
  • the bioactive agent comprises an antibiotic.
  • the antibiotic can be, for example, one or more of Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Streptomycin, Tobramycin, Paromomycin, Ansamycins, Geldanamycin, Herbimycin, Carbacephem, Loracarbef, Carbapenems, Ertapenem, Doripenem, Imipenem/Cilastatin, Meropenem, Cephalosporins (First generation), Cefadroxil, Cefazolin, Cefalotin or Cefalothin, Cefalexin, Cephalosporins (Second generation), Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cephalosporins (Third generation), Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceft, Ceft
  • compositions can be used in a variety of applications, such as cosmetics, agriculture, pharmaceuticals, among others.
  • the compositions can be used as pharmaceutical compositions.
  • the releasable agent will generally be a bioactive agent, but does not have to be.
  • the releasable agent can be a non-bioactive substance and still be used in a pharmaceutical composition.
  • a variety of pharmaceutical compositions comprising the polymer and agent can be conveniently prepared in a desired dosage form, including, for example, a unit dosage form or controlled release dosage form, and prepared by any of the methods well known in the art of pharmacy.
  • compositions are prepared by uniformly and intimately bringing the agent into association with a carrier or a finely divided solid carrier, or both.
  • the polymer itself can be the carrier and/or can be combined with other carriers or additives.
  • Other pharmaceutical carriers can also be used.
  • solid carriers, other than the polymer (if solid) include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers, other than the polymer (if liquid) are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • Other pharmaceutically acceptable carriers or components that can be mixed with the bioactive agent can include, for example, a fatty acid, a sugar, or a salt.
  • Certain polymers of the present invention may be waxy and thus not injectable.
  • these alkyl substituted polylactides can still retain the desirable property of being very hydrophobic and lipophilic in comparison to normal polylactide and polylactide-co-glycolide polymers, thus having an advantage for many applications, including pharmaceutical applications.
  • certain polymers can exhibit better control of drug release, but are not necessarily injectable.
  • a non- injectable alkyl substituted polylactide can be made injectable by admixing a plasticizer or other substance with the alkyl substituted polylactide.
  • a non- injectable alkyl-substituted polylactide can be made injectable by reducing the viscosity of the polymer, for example, with an additive as discussed above, or by heating just prior to administering the injection.
  • the composition can be present in a kit.
  • the kit can comprise a suitable package or container for the compositions. Examples include without limitation sterile packaging. Because the disclosed compositions are suitable for use as injectable compositions, a kit can include a prepackaged injection device, comprising an injection device that is loaded with the composition. Suitable injection devices include without limitation syringes, trochars, and others.
  • compositions can be used to administer a bioactive agent to a subject in need thereof, for example to treat a disorder for which the bioactive agent is effective.
  • the compositions can be administered to any tissue or fluid of a subject.
  • the mode of administration can be any suitable mode, for example parental administration, oral administration, enteral administration, topical administration and the like.
  • the liquid compositions comprising one or more low viscosity polymers can be injected into a subject.
  • the nature of the composition administered will generally be selected based on the desired dosage of the bioactive agent, which will vary greatly depending on the disorder but can be readily determined by one experienced in the pharmaceutical arts.
  • an "effective amount" of a composition refers to an amount of the composition that will achieve a desired therapeutic result.
  • the effective amount will vary greatly depending on the composition, bioactive agent, and disorder or condition that is being treated.
  • the actual effective amount of dosage amount of the composition administered to a subject can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and can depend on the route of administration. Depending upon the dosage and the route of administration, the number of administrations of a preferred dosage and/or an effective amount may vary according to the response of the subject.
  • One of skill in the art can determine an effective amount of a disclosed pharmaceutical composition.
  • a dose can comprise from about 0.01 microgram/kg/body weight, about 0.1 microgram/kg/body weight, about 1 microgram/kg/body weight, about 5 microgram/kg/body weight, about 10 microgram/kg/body weight, about 50 microgram/kg/body weight, about 100 microgram/kg/body weight, about 200 microgram/kg/body weight, about 350 microgram/kg/body weight, about 500 microgram/kg/body weight, about 1 milligram/kg/body weight, about 5 milligram/kg/body weight, about 10 milligram/kg/body weight, about 50 milligram/kg/body weight, about 100 milligram/kg/body weight, about 200 milligram/kg/body weight, about 350 milligram/kg/body weight, about 500 milligram/kg/body weight, to about 1000 mg/kg/body weight or more per administration, and any range derivable therein.
  • a range of about 1 mg/kg/body weight to about 100 mg/kg/body weight, about 5 microgram/kg/body weight to about 500 milligram/kg/body weight, etc. can be administered, based on the numbers described above.
  • the polymers can be used to alter the pharmacokinetics of a bioactive agent.
  • the polymers can be used to reduce the degradation of a bioactive agent.
  • the polymers can also be used to provide more complete, or better controlled, (e.g., as compared to polylactide) release of the bioactive into a subject.
  • compositions can be administered to any desired subject.
  • the subject can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a mammal, for example, a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is a mammal.
  • the subject is a human.
  • compositions can also be administered by any suitable route, including parenterally, topically, orally, enterally, bucally, rectally, sublingually, mucosally, or by inhalation among others.
  • the composition is administered orally.
  • the composition is administered enterally.
  • the composition is applied topically.
  • the composition is administered parenterally.
  • Parenteral administration includes, but is not limited to, intraveneous, intradermal, intramuscular, intraarterial, intrathecal, subcutaneous, intraperitonial, intravitreal administration.
  • the composition can be injected into a subject.
  • the invention is further illustrated by the following non-limiting examples.
  • Tin(II) 2-ethylhexanoate (Sn(Oct) 2 ) was used to polymerize 2-hydroxyoctanoic acid.
  • 2-hydroxyoctanoic acid 0.153 g (3.8 mmol; 0.5 mol% cat.)
  • tin(II) 2-ethylhexanoate were filled into a round-bottom flask followed by addition of the monomer. The flask was connected to a micro-distillation bridge and a vacuum pump.
  • the polymerization was started by heating in a preheated oil- bath to 180 °C under permanent stirring and by increasing the vacuum over 30 minutes to a typical oil-pump vacuum of around 0.001 bar. These conditions were maintained throughout the entire polycondensation reaction.
  • the flask was cooled down to 20 °C and the crude compound was dissolved in 20 mL acetone. The solution was added drop-wise into 0.5 L of a cold (4 °C) mixture of 10 % (v/v) water in ethanol under stirring and was further precipitated at 4 °C for 24 hours.
  • the solution was decanted off and the precipitated polymer was dissolved in acetone and centrifuged for 10 minutes. The supernatant containing the polymer was collected and the solvent was evaporated. Residual solvents were removed at 150 °C under vacuum for 3 hours.
  • the molecular weight of the product hexyl-substituted poly(lactic acid) polymer increases linearly (FIG. 1).
  • the weight-average molecular weight (M w ) was 1120 g/mol after one hour, 5070 g/mol after four hours and 20,220 g/mol after 16 hours.
  • the M w for a smaller 2.5 g scale reaction under the same reaction conditions lead to 53,190 g/mol after 24 hours (Table 1).
  • Table 1 HEX-PLA melt poly condensation with tin(ll) 2-ethylhexanoate (Sn(Oct) 2 ) as polycondensation catalyst.
  • the polydispersities (PD) were around 1.5 for all reactions. A time dependent molecular weight control for hexPLAs up to 20,000g/mol was observed. All melt polycondensations yielded viscous and clear, but yellowish-colored polymers, appearing more pronounced with harsher reaction conditions.
  • Sulfuric acid was used to polymerize 2-hydroxyoctanoic acid.
  • 7.0 g (44 mmol) of 2-hydroxy octanoic acid 0.022 g (2.2 mmol; 0.5 mol% cat.) sulfuric acid (96%) were filled into a round-bottom flask followed by addition of the monomer.
  • the flask was connected to a micro-distillation bridge and a vacuum pump.
  • the polymerization was started by heating in a preheated oil-bath to 150 °C under permanent stirring and by increasing the vacuum over 30 minutes to a typical oil- pump vacuum of around 0.001 bar. These conditions were maintained throughout the entire polycondensation reaction.
  • the flask was cooled down to 20 °C, and the crude compound was dissolved in 20 mL acetone. The solution was added drop- wise into 0.5 L of a cold (4 °C) 0.1 M NaHC0 3 -solution under stirring and was further precipitated at 4 °C for 24 h.
  • the solution was decanted off and the precipitated polymer was dissolved in acetone and transferred into a round bottom flask for removal of acetone and residual water under vacuum.
  • the polymer was again dissolved in acetone and filtered through Celite® 545 coarse. Residual solvents were removed from the purified product at 150 °C under vacuum for 3 hours.
  • Sulfuric acid has good water solubility which can facilitate polymer purification by precipitation into water. Under slightly basic conditions (e.g., addition of 0.1 M NaHC0 3 ) non-reacted monomers become water soluble and can be fully removed. Melt polycondensations catalysed with sulfuric acid and purified with water can lead to pure, clear and colorless, viscous polymers.
  • Sulfuric acid catalysed melt polycondensations facilitate the synthesis of defined molecular weights by controlling the reaction time (FIG. 2).
  • a linear increase in M w was observed during the first 6 hours, followed by a reduced M w increase and leading to a M w of up to 20,000 g/mol for longer reaction times.
  • high yields of 90% of pure colorless hexPLAs were obtained after the aqueous precipitation procedure.
  • Sulfuric acid was used to polymerize 2-hydroxyoctanoic acid.
  • 2-hydroxy octanoic acid For the polymerization reaction of 21.0 g (132 mmol) of 2-hydroxy octanoic acid, 0.066 g (6.6 mmol; 0.5 mol% cat.) sulfuric acid (96%) were filled into a round-bottom flask followed by addition of the monomer. The flask was connected to a micro-distillation bridge and a vacuum pump. The polymerization was started by heating in a preheated oil-bath to 120 °C under permanent stirring and by increasing the vacuum over 30 minutes to a typical oil- pump vacuum of around 0.001 bar. These conditions were maintained throughout the entire polycondensation reaction.
  • the flask was cooled down to 20°C, and the crude compound was dissolved in 20 mL acetone. The solution was added drop-wise into 2 L of a cold (4 °C) 0.1 M NaHC0 3 -solution under stirring and was further precipitated at 4 °C for 24 h.
  • the solution was decanted off and the precipitated polymer was dissolved in acetone and transferred into a round bottom flask for removal of acetone and residual water under vacuum.
  • the polymer was again dissolved in acetone and filtered through Celite® 545 coarse. Residual solvents were removed from the purified product at 120 °C under vacuum for 1 hour.
  • the rheo logical behavior of the three polymers was assessed using a rheometer (Bohlin Instruments CVO 120 high res, Bohlin Instruments, USA) in a 20 mm parallel plate set-up with a gap size of 1 mm. The temperature was maintained at 25 °C and the shear rate was varied in the range between 0.1 1/s and 1000 1/s.
  • FIG. 3 shows the viscosity over shear rate for all three polymers. The polymers show shear-thinning behavior at shear rates higher than 100 1/s and also thixotropy.
  • NMP N-methyl pyrrolidone
  • Example 7 Injectability of hexPLA and formulations with NMP
  • FIG. 6 dispays the release of Haloperidol from formulations with hexPLA.
  • a steady release of Haloperidol from the formulations over 48 hours is observed with the amount of released drug depending on the molecular weight of the polymer.
  • the formulation having a molecular weight of 2,000 g/mol showed the slowest release in comparison to the formulations with higher molecular weight because Haloperidol is dissolvable in the hexPLA matrix and the solubility also is depending molecular weight.

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Abstract

L'invention concerne des compositions comprenant des polymères préparés par polycondensation en masse fondue d'acides 2-hydroxyalkyliques. Des procédés de fabrication et d'utilisation des compositions sont également décrits.
PCT/IB2010/053383 2010-07-26 2010-07-26 Compositions comprenant des polymères préparés à partir d'acides 2-hydroxyalkyliques WO2012014011A1 (fr)

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CA2806351A CA2806351C (fr) 2010-07-26 2010-07-26 Compositions comprenant des polymeres prepares a partir d'acides 2-hydroxyalkyliques
EP10752926.5A EP2598553B1 (fr) 2010-07-26 2010-07-26 Compositions comprenant des polymères préparés à partir d'acides 2-hydroxyalkyliques
DK10752926.5T DK2598553T3 (da) 2010-07-26 2010-07-26 Sammensætninger omfattende polymerer fremstillede af 2-hydroxyalkylsyrer
PCT/IB2010/053383 WO2012014011A1 (fr) 2010-07-26 2010-07-26 Compositions comprenant des polymères préparés à partir d'acides 2-hydroxyalkyliques
JP2013521232A JP6147664B2 (ja) 2010-07-26 2010-07-26 ２−ヒドロキシアルキル酸から調製されたポリマーを含む組成物
ES10752926.5T ES2581837T3 (es) 2010-07-26 2010-07-26 Composiciones que comprenden polímeros preparados a partir de ácidos 2-hidroxi alquil
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130281637A1 (en) * 2012-04-20 2013-10-24 Sucampo Ag Fatty acid derivative-polymer conjugate
US20150293372A1 (en) * 2012-11-29 2015-10-15 Nidec Sankyo Corporation Photographing Optical Device
WO2019145430A1 (fr) 2018-01-26 2019-08-01 Apidel Sa Nouvelles formulations de spironolactone et leur utilisation
EP3656378A1 (fr) 2018-11-26 2020-05-27 ValMeyer Sàrl Nouvelle composition d'amide, esters anesthésiques locaux et leurs utilisations

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9155745B2 (en) 2009-06-16 2015-10-13 Universite De Geneve Bevacizumab formulations with lower aggregation propensity, comprising corticosteroid anti-inflammatory drugs
JP6148701B2 (ja) * 2015-07-31 2017-06-14 ユニベルシテ ドゥ ジュネーブ ２−ヒドロキシアルキル酸から調製されたポリマーを含む組成物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007012979A2 (fr) * 2005-04-22 2007-02-01 Universite De Geneve Compositions de polylactide and leurs utilisations

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3755558A (en) * 1971-02-23 1973-08-28 Du Pont Polylactide drug mixtures for topical application atelet aggregation
ZA918168B (en) * 1990-10-16 1993-04-14 Takeda Chemical Industries Ltd Prolonged release preparation and polymers thereof.
US5856401A (en) * 1993-05-06 1999-01-05 Saam Associates Method of preparing condensation polymers by emulsion polymerization
SE9400918L (sv) * 1994-03-18 1995-09-19 Anne Fjellstad Paulsen Stabiliserad komposition för oral administrering av peptider
CA2192782C (fr) * 1995-12-15 2008-10-14 Nobuyuki Takechi Production de microsphere
FR2748205A1 (fr) * 1996-05-06 1997-11-07 Debio Rech Pharma Sa Compositions pharmaceutiques pour la liberation controlee de principes actifs insolubles
US6689768B2 (en) * 1998-04-15 2004-02-10 Jenapharm Gmbh & Co. Kg Pharmaceutical preparations for treating side effects during and/or after GnRHa therapy
US7041320B1 (en) * 2002-05-31 2006-05-09 Biotek, Inc. High drug loaded injectable microparticle compositions and methods of treating opioid drug dependence

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007012979A2 (fr) * 2005-04-22 2007-02-01 Universite De Geneve Compositions de polylactide and leurs utilisations

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
G. SCHWACH ET AL.: "Influence of polymerization conditions on the hydrolytic degredation of poly(DL-lactide) polymerized in the presence ofstannous octoate or zinc-metal", BIOMATERIALS, vol. 23, 2002, pages 993 - 1002
T. TRIMAILLE ET AL: "Poly(hexyl-substituted lacitdes): Novel injectable hydrophobic drug delivery systems", J. BIOMED. MATERIALS RESEARCH PART A, 2006 - 6 September 2006 (2006-09-06), pages 55 - 65, XP002632171, DOI: 10.1002/jbm.a.30888 *
TRIMAILLE ET AL: "Novel polymeric micelles for hydrophobic drug delivery based on biodegradable poly(hexyl-substituted lactides)", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER BV, NL, vol. 319, no. 1-2, 17 August 2006 (2006-08-17), pages 147 - 154, XP005561677, ISSN: 0378-5173, DOI: DOI:10.1016/J.IJPHARM.2006.03.036 *
YIN M ET AL: "Preparation and Characterization of substituted polylactides", MACROMOLECULES, AMERICAN CHEMICAL SOCIETY, US, vol. 32, no. 23, 1 January 1999 (1999-01-01), pages 7711 - 7717, XP002339171, ISSN: 0024-9297, DOI: DOI:10.1021/MA9907183 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130281637A1 (en) * 2012-04-20 2013-10-24 Sucampo Ag Fatty acid derivative-polymer conjugate
US8835571B2 (en) 2012-04-20 2014-09-16 Sucampo Ag Fatty acid derivative-polymer conjugate
US20150293372A1 (en) * 2012-11-29 2015-10-15 Nidec Sankyo Corporation Photographing Optical Device
US10423003B2 (en) * 2012-11-29 2019-09-24 Nidec Sankyo Corporation Photographing optical device
WO2019145430A1 (fr) 2018-01-26 2019-08-01 Apidel Sa Nouvelles formulations de spironolactone et leur utilisation
EP3656378A1 (fr) 2018-11-26 2020-05-27 ValMeyer Sàrl Nouvelle composition d'amide, esters anesthésiques locaux et leurs utilisations
WO2020109254A1 (fr) 2018-11-26 2020-06-04 ValMeyer Sàrl Nouvelle composition d'anesthésiques locaux d'amide et d'ester et ses utilisations

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US20130131190A1 (en) 2013-05-23
JP6147664B2 (ja) 2017-06-14
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